Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/36—Oxygen or sulfur atoms
  • C07D207/40—2,5-Pyrrolidine-diones
  • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
  • C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/36—Oxygen or sulfur atoms
  • C07D207/40—2,5-Pyrrolidine-diones

Definitions

• R represents an aryl or araliphatic group substituted in the aromatic ring with at least one sulphonamido group, the nitrogen atom of which may be joined to a further ring substituent to form a CO-NHSO chain
• R R R and R are each H, alkyl of 1-5 carbon atoms or an aryl group, at least one of R R R and R being an aryl group and physiologically acceptable salts thereof with bases.
• the compounds are useful in the treatment of epilepsy.
• This invention relates to novel compounds of use in the treatment of epilepsy and to processes for their preparation.
• the compound wethyl-u-methyl-succinimide has been shown to be effective against the petit mal form of epilepsy but it is far less effective against the grand mal form and its efiective dose level then approaches the toxic dose level.
• R R R and R which may be the same or different, are hydrogen atoms, alkyl roups having 1-5 carbon atoms or aryl groups, at least one of the substituents R R R and R being an aryl group) and their salts with bases.
• These compounds possess particularly favorable pharmacological properties as hereinafter set forth including strong anti-convulsant activity and particularly good compatibility. They also exhibit diuretic activity due to possession of a sulphonamido group.
• R may, for example be a phenyl group which in addition to a sulphonamido group, may carry one or more such substituents as aliphatic hydrocarbon groups, e.g. lower alkyl groups for example methyl, ethyl or propyl groups, ether groups such as alkoxy groups having 1-5 carbon atoms, for example methoxy or ethoxy groups, hydroxy groups, acylamido groups, such as formamido, acetamido or diacetamido groups, nitro groups, amino groups, carboxyl groups, acyl groups such as acetyl or benzoyl groups, or halogen atoms.
• substituents as aliphatic hydrocarbon groups, e.g. lower alkyl groups for example methyl, ethyl or propyl groups, ether groups such as alkoxy groups having 1-5 carbon atoms, for example methoxy or ethoxy groups, hydroxy groups, acylamido groups, such as forma
• R is a group of the formula SOgNRR" (II) where R represents one or more hydrogen or halogen atoms, e.g. fluorine, chlorine or bromine atoms, or aliphatic hydrocarbon, ether, hydroxy or acylamino groups and R and R which may be the same or different, are hydrogen atoms, heterocyclic groups such as pyridyl, pyrimidyl or imidazolyl groups or aliphatic hydrocarbon groups which may, if desired, carry substituents such as oxo, hydroxyl, carboxyl or esterified carboxyl, or amino or alkylamino groups, or together with the nitrgen atom to which they are attached, form a heterocyclic group, e.g. a piperidyl or piperazyl group.
• R represents one or more hydrogen or halogen atoms, e.g. fluorine, chlorine or bromine atoms, or aliphatic hydrocarbon, ether, hydroxy or
• R can also advantageously together with NR R' form a CO-NHSO chain.
• R and R may, for example, be alkyl groups having 1-5 carbon atoms, i.e. methyl, ethyl, propyl, butyl or amyl groups, acyl groups such as acetyl or benzoyl groups, carbamyl groups, e.g. the n-butylamino-carbonyl group, hydroxyalkyl groups, e.g. B-hydroxyethyl, or esterified carboxyalkyl groups e.g. ethoxycarbonyl-ethyl groups.
• the preferred compounds, however, are those in which R and R are both hydrogen.
• the sulphonamido group is prefcrably in the 4-position relative to the succinimido group.
• At least one of the substituents R R R and R is an aryl group, that is an aromatic hydrocarbon group which may be unsubstituted or may carry one or more substituents, for example alkoxy, methylenedioxy, nitro, cyano, acyl, carboxyl, esterified carboxyl, amino, alkylamino, sulphonamido or acylamido groups or halogen atoms.
• the aromatic hydrocarbon group may be polynuclear or, more preferably, mononuclear, and the nucleus may carry one or more alkyl, alkenyl or aralkyl groups.
• Alkoxy, alkyl, alkenyl, aralkyl or esterified carboxyl groups preferably contain 1-5- carbon atoms in the aliphatic portion thereof.
• at least one of R R R and R may be a phenyl, chlorophenyl, fluorophenyl methoxyphenyl, nitrophenyl, aminophenyl or acylamidophenyl group.
• One especially useful compound according to the invention is l-N-(or-methyl-a-phenyl-succinimido)-4-su1phonamidobenzene.
• 1-N-( a-methyl-a phenyl succinimido) 4 sulphonamido-benzene has shown excellent anti-convulsant activity in electro-shock tests on mice and rats while its LD value appears to be at least 5000 mg./kg. Some sedative activity can be observed.
• the corresponding ocethyl compound possesses a measurable toxicity but this is still very low, the LD value being of the order of 3000 mg./kg., while its anti-convulsant activity is of the same order as that of the methyl compound.
• the aryl-substituted succinimido compounds accordin to the invention show prolonged duration of action as compared with the corresponding alkyl-succinimido derivatives.
• the new compounds form salts with bases, for example alkali metal salts, e.g. sodium salts or salts with ammonia or amines.
• bases for example alkali metal salts, e.g. sodium salts or salts with ammonia or amines.
• compositions containing one or more compounds according to the invention together with one or more pharmaceutical carriers or excipients.
• compositions may take the form of tablets, dragees, capsules, lozenges, suppositories, ampoules for injection, solutions, etc.
• the carriers or excipients in such compositions may, for example be those conventional for such forms and may include starch, lactose, magnesium stearate, talc, gelatin, sterile water, or suspending, emulsifying dispersing, thickening or flavouring agents.
• Dosage units forms such as tablets, capsules, suppositories or ampoules are preferred and advantageously each unit contains to 1000 mg. of active substances, preferably 100 to 300 mg.
• compositions preferably contain the active substance at a concentration between 0.10 and 80.0% by weight.
• the reaction may be effected in a single stage, or in two stages.
• the initial product will have the general formula 31 BF--CO-NHR RL- CO0H R (or its isomer in which the hemisuccinyl group is attached by the carboyl adjacent to the groups R and R and may be isolated, if desired, before final cyclisation.
• the final condensation requires a reaction temperature of the order of 200 C. and for single stage condensations the reaction should be c i Out a fi 4 order of temperature.
• the half-condensation of the succinic acid of Formula IV generally takes place within the range -l00 C.
• the initial condensation to form the product of Formula V is readily effected by merely heating in an inert solvent, e.g. a hydrocarbon, nitro-hydrocarbon, chloro-hydrocarbon, ether or cyclic ether solvent.
• an inert solvent e.g. a hydrocarbon, nitro-hydrocarbon, chloro-hydrocarbon, ether or cyclic ether solvent.
• the second stage to effect cyclisation may be effected, for example, in the presence of a dehydrating agent such as an anhydrous salt, e.g. sodium acetate or sulphuric, phosphoric or polyphosphoric acid or phosphorus pentoxide or simply by heating to about 200 C. in the absence of a solvent with or without a vacuum.
• the reaction time for the reaction with the free acid is preferably 1-5 hours, advantageously about 2 hours.
• the one-stage reaction with the anhydride is preferably effected at about 200 C. for a short time.
• the amine RNH may carry substituents capable of conversion to the desired substituents in R after cyclisation.
• 6-amino-saccharin may be reacted with the acid of Formula IV or its anhydride to give a compound in which R carries adjacent sulphonamide and carboxyl groups, the cyclic amide ring having been split during the reaction.
• a nitro group initially in the group R may be reduced by catalytic hydrogenation, to an amino group which may itself be alkylated or acylated by reaction with an alkylating or acylating reagent.
• the sulphonamido compounds according to the invention may also be prepared from corresponding compounds lacking a sulphonamido group by reaction with reagents for introducing a sulphonamido group.
• a compound of Formula I in which R represents an aryl or araliphatic group having no sulphonamido group may be reacted with a sulphonyl halide, to form a halosulphonyl derivative which may then be reacted with ammonia or an amine of the formula NH-R R where R and R" have the above meanings.
• acylation gives the acyl derivative e.g. by reaction with an acyl halide or anhydride
• alkylation gives the alkyl derivatives, e.g. by reaction with an alkyl halide, sulphate, sulphonate etc.
• Hydroxyalkylation gives the hydroxyalkyl derivative, e.g. by reaction with ethylene oxide
• carbamylation gives the corresponding urethane, e.g. by reaction with a carbonyl dihalide followed by reaction with ammonia or an amine.
• EXAMPLE 1 1-N-( a-phenyl-a-Inethyl-succinimido) -4-sulphonamidobenzene 17.2 g. sulphanilamide and 20.8 g. a-phenyl-a-methyl-succinic acid are heated together to 200 C. and held at this temperature for 30 minutes. Then ethyl acetate is added and the are heated together to 190 C. and held at that temperature for minutes. The mixture is then taken up in ethyl acetate and filtered over activated charcoal. Petrol ether is added to the filtrate, which is cooled and the precipitate filtered with suction to yield:
• EXAMPLE 4 l-N-(u-p-chlorophenyl-u-methyl-succinimido)-4- sulphonamido-benzene 22.2 g. of a-methyl-u-p-chlorophenyl-succinic acid and 15.7 g. of sulphanilamide are heated together for 30 minutes at 180-200 C. After cooling the mixture is taken up in ethyl acetate and filtered off from a small amount of insoluble material. The filtrate is cooled and filtration with suction yields 27.6 g. of a light-brown product of m. pt. 193-200" C.
• EXAMPLE 5 l-N-u-phenylsuccinimido-4-sulphonamido-benzene 11 g. of a-phenyl-succinic acid and 10.4 g. of sulphanilamide are heated together for 25 minutes at 180 C. The oxide product, crystallising on cooling, is then dissolved in acetone and filtered off. Petroleum ether is added to the filtrate which is cooled and on filtration by suction yields 12.4 g. of white crystals of 111. pt. 2l5-217 C.
• EXAMPLE 7 1-N-( a-p-sulphonamido-phenyl-a-methyl-succinimido)-4- sulphonamido-benzene 2.0 g. (0.0075 mol) of a a-phenyl-u-methyl-succinimido-benzene are mixed with 6.0 g. (0.005 mol) of chlorosulphonic acid and heated for 5 minutes to 120 C. Ice is added to the crude reaction product and the precipitate formed filtered with suction. Conc. ammonia is poured in excess over the filter residue which is then gently heated on a water bath. A resinous lump is formed which, after recrystallisation from hot water, yields 0.7 g. of white crystals of :11. pt. 140-143 C.
• EXAMPLE 8 l-N-(a-p-nitrophenyl-a-methyl-succinimido)-4- sulphonamido-benzene 7.4 g. of sulphanilamide 1 mol) and 11.2 g. of u-p-nitrophenyl-u-methyl-succinic acid are heated under a nitrogen atmosphere in an open flask to 180 C. and held at this temperature for 15 minutes. Ethyl acetate is then liberally poured into the melt and the solution is then allowed to cool; the precipitate is then filtered with suction to yield 4.6 g. of brown-red crystals of m. pt. 222-223 C.
• the crystalline product is thoroughly triturated with 2HHC1, filtered with suction and dried. The residue is dissolved in tetrahydrofuran, filtered over activated charcoal and a large amount of ether added.
• EXAMPLE 10 l-N-(a,u-diphenyl-succinicimido)-4-sulphonamidobenzene 1.6 g. of a-diphenylsuccinic acid and 1.0 g. of sulphanilamide (1 mol) 1.8 g. of beige crystals of 111. pt. 220-223 C.
• EXAMPLE 13 1-N- u-p-aminophenyl-u-methyl-succinimido -4- sulph'onamido-benzenc 10. 5 g. of l-N-(a-p-nitrophenyl)-u-methyl-succinimido- 4-sulphonamido-benzene are dissolved in 2.50 ml. of tetrahydrofuran and 3 spatula tips (10 mg.) of PtO are added, followed by hydrogenation.
• EXAMPLE 14 l-N-(u-p-acetamido-phenyl-a-methyl-succinimido)-4- sulphonamido-benzene 0.5 g. of l-N-(a-p-aminophenyl-u-methyl-succinylimido)- 4-sulphamido-benzene and 10 ml. of acetic acid anhydride are heated together until a clear solution is formed. After cooling, ether is added and the precipitate thoroughly cooled and then filtered with suction.
• EXAMPLE 16 l-N- (a-phenyl-a-methyl-succinimido) -3-sulphonamidobenzene 4.0 g. of phenyl-m-methyl-succinic anhydride and 4.0 g. of m-sulfanilamide are heated together for 20 minutes at 210 C. Subsequently, while still hot, the product is dissolved in alcohol and then allowed to stand at room temperature. The precipitated mass of crystals is treated with diethylether and filtered with suction. Recrystallisation from alcohol yields white crystals of m. pt. 177-l79 C. Recrystallisation from petroleum ether yields white crystals of m. pt. 180-182 C.
• R R R and R are each H, alkyl of 1-5 carbon atoms, phenyl or phenyl substituted by at least one of alkyl of 1-5 carbon atoms, alkenyl of up to 5 carbon atoms, alkoxy of 1-5 carbon atoms, methylenedioxy, nitro, cyano, carboxyl, amino, alkylamino wherein the alkyl radical is of 1-5 carbon atoms, sulphonamido, acetamido or halo, at least one of R R R and R being said phenyl or substituted phenyl, R is at least one of H, halo or hydroxy and R and R are each H, pyrimidyl, alkyl of 1-5 carbon atoms, acetyl, fi-hydroxyethyl, n-butylcarbamy
• R R R and R is phenyl, chlorophenyl, fluorophenyl, methoxyphenyl, nitrophenyl, aminophenyl or acetamidophenyl.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Supports Or Holders For Household Use (AREA)

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Cited By (3)

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• 1966
  • 1966-12-23 GB GB57731/66A patent/GB1181366A/en not_active Expired
• 1967
  • 1967-12-13 NO NO00170971A patent/NO128961B/no unknown
  • 1967-12-14 GR GR670135656A patent/GR35656B/el unknown
  • 1967-12-20 FR FR1583185D patent/FR1583185A/fr not_active Expired
  • 1967-12-21 AT AT885669A patent/AT286977B/de not_active IP Right Cessation
  • 1967-12-21 DK DK642767AA patent/DK136116B/da unknown
  • 1967-12-21 AT AT1157567A patent/AT289095B/de not_active IP Right Cessation
  • 1967-12-22 FI FI3437/67A patent/FI53817C/fi active
  • 1967-12-22 NL NL6717606A patent/NL6717606A/xx unknown
  • 1967-12-22 SE SE17752/67A patent/SE331680B/xx unknown
  • 1967-12-22 CH CH430571A patent/CH553777A/xx not_active IP Right Cessation
  • 1967-12-22 CH CH1804967A patent/CH513154A/de not_active IP Right Cessation
  • 1967-12-22 ES ES348528A patent/ES348528A1/es not_active Expired
  • 1967-12-22 BE BE708473D patent/BE708473A/xx unknown
  • 1967-12-23 DE DE1967G0052015 patent/DE1695104B2/de active Granted
• 1968
  • 1968-03-20 FR FR144497A patent/FR7371M/fr not_active Expired
• 1971
  • 1971-08-04 US US00169063A patent/US3775401A/en not_active Expired - Lifetime

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